Identification and Functional Characterization of a Stable, Centrally Active Derivative of the Neurotensin (8−13) Fragment as a Potential First-in-Class Analgesic
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- 作者：Francis M. Hughes ; Jr. ; Brooke E. Shaner ; Lisa A. May ; Lyndsay Zotian ; Justin O. Brower ; R. Jeremy Woods ; Michael Cash ; Dustin Morrow ; Fabienne Massa ; Jean Mazella ; Thomas A. Dix
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：June 24, 2010
- 年：2010
- 卷：53
- 期：12
- 页码：4623-4632
- 全文大小：973K
- 年卷期：v.53,no.12(June 24, 2010)
- ISSN：1520-4804
文摘
The neurotensin hexapapetide fragment NT(8−13) is a potent analgesic when administered directly to the central nervous system but does not cross the blood−brain barrier. A total of 43 novel derivatives of NT(8−13) were evaluated, with one, ABS212 (1), being most active in four rat models of pain when administered peripherally. Compound 1 binds to human neurotensin receptors 1 and 2 with IC50 of 10.6 and 54.2 nM, respectively, and tolerance to the compound in a rat pain model did not develop after 12 days of daily administration. When it was administered peripherally, serum levels and neurotensin receptor binding potency of 1 peaked within 5 min and returned to baseline within 90−120 min; however, analgesic activity remained near maximum for >240 min. This could be due to its metabolism into an active fragment; however, all 4- and 5-mer hydrolysis products were inactive. This pharmacokinetic/pharmacodynamic dichotomy is discussed. Compound 1 is a candidate for development as a first-in-class analgesic.